Thyroid dysfunction in preterm infants born before 32 gestational weeks.

BACKGROUND: Thyroid hormones are critical for growth and brain development during the newborn period and infancy. Because of delayed maturation of the hypothalamic-pituitary-thyroid axis in preterm infants, thyroid dysfunction is common, and thyroid stimulating hormone (TSH) elevation is often delayed in preterm infants. The objective of this study was to determine the incidence of thyroid dysfunction requiring levothyroxine treatment and to identify its risk factors in preterm infants. METHODS: A retrospective cohort study was performed on preterm infants who were born before 32 gestational weeks and admitted to a single tertiary academic center for more than 8 weeks between January 2008 and December 2014. In these infants, serial thyroid function tests (TFTs) measuring serum TSH and free thyroxine (fT4) were routinely performed at 1, 3, and 6 weeks of postnatal age. RESULTS: Of the 220 preterm infants enrolled, 180 infants underwent TFTs at 1, 3, and 6 weeks of postnatal age and were included in the study. Of the 180 infants, 35 infants (19.4%) were started on levothyroxine treatment based on the results of serial TFTs. Among the 35 infants who were treated with levothyroxine, 16 infants (45.7%) had normal results on the initial TFT. Three of these 16 infants continued to have normal results on the second TFT. Thyroid dysfunction requiring levothyroxine treatment was significantly associated with maternal pregnancy-induced hypertension (adjusted odds ratio 2.64, 95% confidence interval 1.02-6.81). CONCLUSIONS: Thyroid dysfunction requiring levothyroxine treatment occurred in nearly one-fifth of preterm infants born before 32 gestational weeks. Nearly half of the preterm infants who were treated with levothyroxine had normal TSH and fT4 levels at 1 week of postnatal age. The findings of the present study suggest that serial TFTs is important to find preterm infants who require levothyroxine treatment.

Contributions of CAG repeat length in the androgen receptor gene and androgen profiles to premature pubarche in Korean girls.

The CAG repeat length of the androgen receptor (AR) gene, which exhibits an inverse relationship to AR sensitivity, might influence the development of the pubarche along with hyperandrogenemia. There are ethnic differences in the AR CAG repeat length, however, no Asian studies on premature pubarche (PP) have been reported, including Korea. Our objectives were to examine the hormone levels and AR CAG repeat length, and to assess their contributions to PP in Korean girls. Subjects with PP (n=16) and normal pubarche (NP, n=16), and normal controls (NC, n=16) were enrolled. The levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), and free testosterone (FT) were checked. The methylation-weighted (MW) average CAG repeat lengths were analyzed. The median ages at pubarche were 7.4 and 8.9 years in the PP and NP groups, respectively, and the levels of 17-OHP, DHEAS, and FT were similar in both groups. The PP group exhibited a higher DHEAS:DHEA ratio than the NP group (P=0.014). The medians of the MW average CAG repeat length of the AR gene were 22.4 for all subjects and did not differ among the PP (22.3), NP (22.4), and NC (22.2) groups. The AR CAG repeat lengths in the PP and NP groups did not correlate with DHEAS or FT levels. These results suggest that the AR CAG repeat length was not involved in the development of PP in Korean girls. However, excessive adrenal androgen levels, particularly those caused by increased sulfotransferase activity, might be important in the pathogenesis of PP.

Factors Associated with the Presence and Severity of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Korean Children and Adolescents.

The aim of this study was to identify the risk factors for presence and severity of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in Korean children and adolescents. A retrospective chart review of children and adolescents newly diagnosed with T1DM was conducted in seven secondary and tertiary centers in Korea. Eligible subjects were < 20 years of age and had records on the presence or absence of DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, height, body weight, pubertal status, family history of diabetes, delayed diagnosis, preceding infections, health insurance status, and parental education level. A total of 361 patients (male 46.3%) with T1DM were included. Overall, 177 (49.0%) patients presented with DKA at T1DM diagnosis. Risk factors predicting DKA at T1DM diagnosis were age ≥ 12 years, lower serum C-peptide levels, presence of a preceding infection, and delayed diagnosis. Low parental education level and preceding infection increased the severity of DKA. These results suggest that alertness of the physician and public awareness of diabetes symptoms are needed to decrease the incidence and severity of DKA at T1DM diagnosis.

Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy.

The aim of this study was to evaluate the incidence of thyroid dysfunction during valproic acid (VPA) therapy in children and adolescents with epilepsy. The serum levels of thyroid-stimulating hormone (TSH), free thyroxine, and triiodothyronine were evaluated in 61 children with epilepsy who received VPA monotherapy for more than 6 months and in 144 controls. We analyzed the effect of age, seizure type, duration of VPA treatment, dose of VPA, and serum level of VPA on thyroid function. The incidence of subclinical hypothyroidism was significantly higher in patients with VPA therapy than in controls (52.4 vs. 16.7%; p < 0.001). In addition, of the 61 patients, 5 (8.1%) exhibited TSH levels that were >10 µIU/mL. However, none of the patients and controls showed overt hypothyroidism. Serum VPA level and daily dose of VPA were correlated with TSH level. Subclinical hypothyroidism developed frequently in children and adolescents during VPA therapy.

Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.

OBJECTIVE: Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus. DESIGN: Investigation of clinical characteristics and molecular analysis in PHP and PPHP. PATIENTS: Fourteen subjects from 13 unrelated families including subjects with PPHP (n = 1), PHP-Ia (n = 6) and PHP-Ib (n = 7) were enrolled. MEASUREMENTS: Clinical data, including age at presentation, presenting symptom, auxological findings, family history, presence of Albright hereditary osteodystrophy (AHO) features and hormonal and biochemical findings, were analysed. The GNAS locus was subjected to direct sequencing and methylation analysis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). RESULTS: Of the 13 PHP subjects, 10 (three PHP-Ia and seven PHP-Ib) presented with hypocalcemic tetany at ages ranging from 7 to 14·8 years. Subcutaneous calcification was observed as an early manifestation of AHO in one PHP-Ia patient (age, 2·9 years) and one PPHP patient (age, 7 months). Six PHP-Ia and one PPHP harboured four different heterozygous mutations within the coding region of GNAS, p.Asp189_Tyr190delinsMetfxX14, p.Val117fsX23, p.Tyr190CysfsX19, and a splicing mutation (c.659 + 1G>A), of which the latter two were novel. Five subjects with PHP-Ib exhibited complete loss of the maternal-specific methylation pattern. The remaining two PHP-Ib showed a loss of methylation of exon 1A on the maternal allele as a consequence of heterozygous 3-kb microdeletions within the STX16 gene. CONCLUSIONS: GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.

Independent relationships of obesity and insulin resistance with serum proinsulin level in prepubertal children with normal glucose tolerance.

OBJECTIVES: We compared the fasting serum proinsulin levels in lean, overweight, and obese prepubertal children with normal glucose tolerance (NGT). We also evaluated the relationship between fasting proinsulin level and indices of insulin resistance (IR). SUBJECTS AND METHODS: One hundred nine prepubertal children (mean age, 8.6 yr) with NGT were included. The indices of IR included the homeostasis model assessment of IR (HOMA-IR) and adiponectin level. We recorded the presence of one or more of the following metabolic derangements: triglycerides ≥ 150 mg/dL, HDL-cholesterol < 35 mg/dL, and hypertension. RESULTS: Fasting proinsulin levels significantly increased with body mass index (BMI) category from lean (n = 52, 7.22 ± 3.01 pmol/L) to overweight (n = 14, 12.31 ± 2.91 pmol/L) to obese (n = 43, 16.51 ± 7.27 pmol/L) (p < 0.001), after controlling for HOMA-IR. The ratio of the fasting levels of proinsulin to insulin did not differ significantly between the three groups. Both BMI z-score and HOMA-IR were significant independent factors related to the fasting proinsulin level (p < 0.001 for each). A significant inverse association was found between fasting proinsulin level and adiponectin level (r = -0.464, p < 0.001). Children with NGT who had at least one metabolic derangement had higher proinsulin levels than those without metabolic derangement. CONCLUSIONS: Obesity itself or obesity-related IR may independently impose ß-cell overload on prepubertal children with NGT, leading to hyperproinsulinemia without causing failure to convert proinsulin to insulin when some degree of IR and metabolic derangement appears.

Short-term efficacy of 1-month and 3-month gonadotropin-releasing hormone agonist depots in girls with central precocious puberty.

PURPOSE: Gonadotropin-releasing hormone agonist (GnRHa) has been the mainstay of central precocious puberty (CPP) treatment for decades, but few reports have compared the efficacy of 1-month and 3-month depot GnRHa formulations. This study investigates the short-term efficacy of 1-month and 3-month GnRHa depots in girls with CPP. METHODS: Overall, 150 girls with CPP were included in a retrospective review of medical records. Subjects in group 1 (n=105) were treated with 1-month GnRHa depots for ≥12 months, and those in group 2 (n=45) were treated with 1-month GnRHa depots for 6 months followed by 3-month GnRHa depots for ≥6 months. Anthropometric and biochemical data were compared between the groups at 3-time points (after 0, 6, and 12 months of GnRHa treatment). RESULTS: Demographic and clinical characteristics did not differ between the groups at baseline or after 6 months of GnRHa treatment. After 12 months of GnRHa treatment, patients in the both groups showed no difference in bone age (BA), chronological age (CA), BA-CA difference, height standard deviation score (SDS) for CA and BA, or body mass index SDS for CA and BA. The sexual maturity rate of the breast was prepubertal at 12 months in most of subjects. GnRH-stimulated luteinizing hormone (LH) level was suppressed during GnRHa treatment in both groups at 6 and 12 months, although the LH level in group 2 was higher than that in group 1. CONCLUSION: Treating CPP with a 3-month GnRHa depot showed short-term efficacy comparable to that with a 1-month depot in anthropometric parameters and pubertal suppression.

Maternal Hyperglycemia during Pregnancy Increases Adiposity of Offspring.

BACKGROUND: The effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined. METHODS: The body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI). RESULTS: BMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2 ). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values. CONCLUSION: Intrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.

The association of variable number of tandem repeats of the insulin gene with susceptibility to type 1 diabetes among Korean subjects.

BACKGROUND: There is ethnic variation in the variable number of tandem repeats of the insulin gene (INS VNTR), one of the susceptibility loci for developing type 1 diabetes (T1D). We evaluated the influence of the genotypes and subdivisions of INS VNTR on the development of T1D in Korean subjects. METHODS: The study included 352 Korean patients, under the age of 18 years who were diagnosed as having T1D, and 356 control subjects. The insulin - 23HphI A/T single nucleotide polymorphism was used as a marker of class I and III alleles. Surrounding polymorphisms at nucleotide positions + 1127, + 1140, + 2331 and + 2336 were determined as subdivisions of INS VNTR. RESULTS: Classes I/I, I/III and III/III were observed at frequencies of 95.8, 4.2 and 0% among all subjects, respectively. Class I/III genotype was significantly less frequent in patients with T1D than in controls (2.56 versus 5.90%; odds ratio 0.419; P = 0.039). In a subdivision analysis, the ID/ID genotype was decreased among patients (P = 0.017, adjusted P = 0.085) and the IC allele tended to increase. The frequency of the class I/III genotype was significantly lower among patients who were diagnosed when younger than 7 years of age than in controls (odds ratio 0.115; P = 0.011). CONCLUSIONS: INS VNTR has predominance of class I over class III alleles and is associated with susceptibility to T1D in Koreans. In addition, INS VNTR shows distinctive susceptibility according to the age at the onset of T1D.

The durability and effectiveness of sensor-augmented insulin pump therapy in pediatric and young adult patients with type 1 diabetes.

PURPOSE: Despite the prevalent use of insulin pump therapy worldwide, few studies have been conducted among young patients with type 1 diabetes (T1D) in Korea. We investigated the durability and effectiveness of insulin pump therapy among Korean pediatric and young adult patients with T1D. METHODS: This study included 54 patients with T1D diagnosed at pediatric ages (range, 1.1-14.1 years) who initiated insulin pump therapy during 2016-2019 at Seoul National University Children's Hospital and Seoul National University Bundang Hospital. Clinical and biochemical data, including anthropometric measurements, insulin dose, and glycated hemoglobin (HbA1c) levels were obtained from T1D diagnosis to last follow-up. RESULTS: Forty-four patients (81.5%) continued insulin pump therapy with a median pump use duration of 2.9 years (range, 0.2-3.5 years); 10 discontinued the therapy within 12 months (<1 month, n=6; 1-6 months, n=1; and 6-12 months, n=3) due to physical interferences or financial problems. Older age (≥10 years of age) and longer diabetes duration (≥2 years) at the initiation of pump therapy were associated with discontinuation (P<0.05 for both). For patients continuing pump therapy, HbA1c levels significantly decreased after 1 year of therapy (from 8.9% to 8.1%, P<0.001) without changes in the body mass index z-scores or insulin dose. Although 4 patients experienced diabetic ketoacidosis, all recovered without complications. CONCLUSION: Insulin pump therapy was effective in improving glycemic control in T1D patients during 12 months of treatment. Early initiation of insulin pump therapy after T1D diagnosis was helpful for continuing therapy.

High incidence of thyroid dysfunction in preterm infants.

To determine the validity of a repeat thyroid function test for preterm infants, and to investigate factors that influence thyroid function of preterm infants, thyroid functions of 105 infants born at <32 weeks' gestational age were evaluated. Initial serum free thyroxine (fT4) and thyrotropin (TSH) levels were measured during the first 10 days of life, and repeated tests were performed more than 2 weeks apart. We analyzed the effects of gestational age, systemic diseases, and nutrition on the development of thyroid dysfunction. Thirty-one infants (30%) had low fT4 levels (<0.7 ng/dL) in the absence of elevated TSH levels (<7 microU/mL). Thirteen infants (12%) had hypothyroidism (fT4 <0.7 ng/dL, TSH >or=10 microU/mL) and mean age at diagnosis was 28+/-17 days. Twelve infants had moderately elevated TSH (TSH 10-30 microU/mL) with normal fT4 levels after 1 week of postnatal life. The history of undergone surgical procedure which needed iodine containing disinfectants was significantly frequent in the infant with hypothyroidism and transient TSH elevation. Repeated thyroid function tests are necessary for preterm infants, even though they initially show normal thyroid function, and are especially important for infants who have been exposed to excessive or insufficient levels of iodine.

Screening and management of thyroid dysfunction in preterm infants.

Preterm infants can suffer various thyroid dysfunctions associated with developmental immaturity of the hypothalamic-pituitary-thyroid axis, postnatal illness, medications, or iodine supply. The incidence of thyroid dysfunction among preterm infants is higher than that among term infants and has been increasing with improvement in the survival of preterm infants. Hypothyroxinemia is frequently observed during the first week of life in extreme preterm neonates, and the incidence of delayed thyrotropin elevation is high at the age of 2-6 weeks. Although the necessity of routine rescreening remains controversial, recent guidelines on screening for congenital hypothyroidism have recommended rescreening of all preterm neonates. Thyroid hormone replacement is recommended for persistent thyrotropin elevation with or without hypothyroxinemia. Hypothyroxinemia without thyrotropin elevation does not require treatment, and some potential risks of levothyroxine supplementation have been reported. Although most thyroid dysfunctions are transient, careful follow-up after discontinuation of levothyroxine is considered so as to avoid missing persistent hypothyroidism.

How can the occurrence of delayed elevation of thyroid stimulating hormone in preterm infants born between 35 and 36 weeks gestation be predicted?

OBJECTIVE: We evaluated frequency and risk factors of delayed TSH elevation (dTSH) and investigated follow-up outcomes in the dTSH group with venous TSH (v-TSH) levels of 6-20 mU/L according to whether late preterm infants born at gestational age (GA) 35-36 weeks had risk factors. METHODS: The medical records of 810 neonates (414 boys) born at Seoul National University Hospital who had a normal neonatal screening test (NST) and underwent the first repeat venous blood test at 10-21 days post birth were reviewed. RESULTS: Seventy-three (9.0%) neonates showed dTSH, defined as a v-TSH level ≥6.0 mU/L, 12 of whom (1.5%) were started on levothyroxine medication. A multivariate-adjusted model indicated that a low birth weight (LBW <2,000 g), a congenital anomaly, and exposure to iodine contrast media (ICM) were significant predictors for dTSH (all p < 0.05). Among these 73 dTSH infants, all 5 infants with TSH levels ≥20 mU/L began levothyroxine medication, and 6 of 16 infants with v-TSH levels of 10-20 mU/L were indicated for levothyroxine, regardless of coexisting risk factors. However, only 1 of 52 infants with v-TSH levels of 6-10 mU/L who had a congenital anomaly was indicated for levothyroxine. All healthy late preterm infants, including LBW and multiple births, with v-TSH levels of 6-10 mU/L exhibited normal thyroid function. CONCLUSIONS: dTSH was detected in 9.0% and levothyroxine was indicated in 1.5% of infants born at GA 35-36 weeks, particularly those with a LBW, a congenital anomaly, or history of ICM exposure. Either levothyroxine or retesting is indicated for late preterm neonates with TSH levels ≥10 mU/L regardless of risk factors. If healthy preterm neonates show v-TSH levels of 6-10 mU/L, a second repeat test may not be necessary; however, further studies are required to set a threshold for retesting.

Pregnancy Outcomes of Women Additionally Diagnosed as Gestational Diabetes by the International Association of the Diabetes and Pregnancy Study Groups Criteria.

BACKGROUND: We investigated the pregnancy outcomes in women who were diagnosed with gestational diabetes mellitus (GDM) by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria but not by the Carpenter-Coustan (CC) criteria. METHODS: A total of 8,735 Korean pregnant women were identified at two hospitals between 2014 and 2016. Among them, 2,038 women participated in the prospective cohort to investigate pregnancy outcomes. Diagnosis of GDM was made via two-step approach with 50-g glucose challenge test for screening followed by diagnostic 2-hour 75-g oral glucose tolerance test. Women were divided into three groups: non-GDM, GDM diagnosed exclusively by the IADPSG criteria, and GDM diagnosed by the CC criteria. RESULTS: The incidence of GDM was 2.1% according to the CC criteria, and 4.1% by the IADPSG criteria. Women diagnosed with GDM by the IADPSG criteria had a higher body mass index (22.0±3.1 kg/m² vs. 21.0±2.8 kg/m², P<0.001) and an increased risk of preeclampsia (odds ratio [OR], 6.90; 95% confidence interval [CI], 1.84 to 25.87; P=0.004) compared to non-GDM women. Compared to neonates of the non-GDM group, those of the IADPSG GDM group had an increased risk of being large for gestational age (OR, 2.39; 95% CI, 1.50 to 3.81; P<0.001), macrosomia (OR, 2.53; 95% CI, 1.26 to 5.10; P=0.009), and neonatal hypoglycemia (OR, 3.84; 95% CI, 1.01 to 14.74; P=0.049); they were also at an increased risk of requiring phototherapy (OR, 1.57; 95% CI, 1.07 to 2.31; P=0.022) compared to the non-GDM group. CONCLUSION: The IADPSG criteria increased the incidence of GDM by nearly three-fold, and women diagnosed with GDM by the IADPSG criteria had an increased risk of adverse pregnancy outcomes in Korea.

Excessive Iodine Intake and Subclinical Hypothyroidism in Children and Adolescents Aged 6-19 Years: Results of the Sixth Korean National Health and Nutrition Examination Survey, 2013-2015.

BACKGROUND: Iodine is an important element for the synthesis of thyroid hormone, and its deficiency or excessive intake is associated with various thyroid diseases. Little is known about the association between iodine status and thyroid function among children and adolescents living in iodine-rich areas. Therefore, this study analyzed this association using data from a nationwide survey. METHODS: From the Korea National Health and Nutrition Examination Surveys VI (2013-2015) data, 1288 subjects (711 male) aged 6-19 years who underwent a urinary iodine concentration (UIC) test and 1000 subjects (564 male) aged 10-19 years who underwent a thyroid function test were included in this study. Serum levels of thyrotropin (TSH), free thyroxine (fT4), and thyroperoxidase antibodies (TPOAb) were analyzed. Subclinical hypothyroidism (SCH) was defined as TSH >5.5 µIU/mL with a normal fT4 level. Median daily iodine intake was calculated from the UIC. Daily sodium intake was derived from the nutritional survey data of 1181 subjects. RESULTS: The median UIC was 449 µg/L (range 15-21,905 µg/L), and the prevalence rates of UIC ≥300 µg/L and ≥1000 µg/L were 64.9% and 25.0%, respectively. The prevalence rates of a sodium intake >2000 mg/day and iodine intake >2400 µg/day were 75.0% (885/1181) and 12.7% (164/1288), respectively. The prevalence rates of SCH and TPOAb >34 IU/mL were 7.2% (72/1000) and 2.3% (23/1000), respectively. The prevalence of SCH was significantly higher in the iodine deficient and iodine excess groups compared to those in the UIC 100-299.9 µg/L group (p = 0.038). Therefore, there was a U-shaped and inverted U-shaped correlation between serum levels of TSH and fT4 with UIC, respectively. These correlations were especially prominent when UIC was >1000 µg/L. There was no definite correlation between TPOAb and UIC. CONCLUSIONS: Excess iodine was prevalent in Korean children and adolescents, and it may be associated with SCH. Therefore, monitoring the iodine status and education on adequate intake are needed in iodine-rich areas.

Three-year follow-up of children with abnormal newborn screening results for congenital hypothyroidism.

BACKGROUND: To analyze predictive factors suggesting transient congenital hypothyroidism (TCH) compared to permanent congenital hypothyroidism (PCH) or transient thyroid function test (TFT) abnormalities among children who had positive screening results at our centers over the past decade. METHODS: A retrospective chart review of 105 subjects who presented elevated TSH levels on a newborn screening test (NST) was done. TCH was defined when a trial-off therapy was successful, and PCH was defined when a trial failed or when the subject was kept on medication beyond 3 years of age. A transient TFT abnormality was defined when follow-up TFTs were normalized without levothyroxine (LT4) therapy. RESULTS: Congenital hypothyroidism (CH) was diagnosed in 75.2% (TCH 35.2% and PCH 40.0%) of all subjects; the others (24.8%) showed transient TFT abnormalities. Initial NST-TSH levels (optimal cutoff point, 31.0 µIU/mL), the LT4 dose at 2 years of age (4.1 µg/kg/day), and the maximal LT4 dose (50 µg/day) merged as significant predictive factors discriminating between TCH and PCH. The initial serum level of free T4 (1.06 ng/dL) and not TSH (27.2 µIU/mL) was the only discriminating factor between transient TFT abnormalities and TCH. CONCLUSION: Earlier re-evaluation might be possible when a patient's initial NST-TSH levels and maximal or 2-year LT4 doses are low, as both are important predictors of successful trial-off therapy in CH patients. When the initial serum level of free T4 is above the average value in neonates with mildly elevated TSH levels, TFTs may be more likely to normalize on their own.

DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes.

Intrauterine exposure to hyperglycemia is reported to confer increased metabolic risk in later life, supporting the 'developmental origins of health and disease' hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. In this study, we compared pairwise DNA methylation differences between siblings whose intrauterine exposure to maternal gestational diabetes (GDM) were discordant. Methylation of peripheral blood DNA of 18 sibling pairs was measured using Infinium HumanMethylation450 BeadChip assays. Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate <0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at HNF4A showed inverse correlations with mRNA expression levels, though non significant. In a gene set enrichment analysis, metabolism and signal transduction pathways were enriched. In conclusion, we found DNA methylation markers associated with intrauterine exposure to maternal GDM, including those within genes previously implicated in diabetes or obesity.

Multiple osteoblastomas in a child with Cushing syndrome due to bilateral adrenal micronodular hyperplasias.

Adrenocorticotropin-independent adrenal hyperplasias are rare diseases, which are classified into macronodular (>1 cm) and micronodular (≤1 cm) hyperplasia. Micronodular adrenal hyperplasia is subdivided into primary pigmented adrenocortical disease and a limited or nonpigmented form 'micronodular adrenocortical disease (MAD)', although considerable morphological and genetic overlap is observed between the 2 groups. We present an unusual case of a 44-month-old girl who was diagnosed with Cushing syndrome due to MAD. She had presented with spotty pigmentation on her oral mucosa, lips and conjunctivae and was diagnosed with multiple bone tumors in her femur, pelvis and skull base at the age of 8 years. Her bone tumor biopsies were compatible with osteoblastoma. This case highlights the importance of verifying the clinicopathologic correlation in Cushing syndrome and careful follow-up and screening for associated diseases.

Clinical and laboratory characteristics of neonatal hypocalcemia.

PURPOSE: To describe the clinical characteristics of full-term neonates with hypocalcemia and to suggest factors associated with neonatal hypocalcemia. METHODS: The medical records of full-term neonates with hypocalcemia were reviewed. Hypocalcemia was defined as an ionized calcium (iCa) concentration of <4 mg/dL. Parathyroid hormone (PTH) insufficiency was defined as a serum PTH level of <60 pg/mL or a serum phosphorus level higher than the serum calcium level in the presence of hypocalcemia. RESULTS: Fifty-three neonates were enrolled. The median age at diagnosis of hypocalcemia was 3 days. In all the neonates, formula feeding predominance was observed. Thirty-eight neonates (69.8%) were compatible with PTH insufficiency. The number of formula-fed neonates was significantly higher than that of breast-fed patients among neonates with PTH insufficiency (P=0.017). Intact PTH was negatively correlated with serum phosphorus levels. Twelve out of 14 neonates (85.7%) had 25-hydroxy vitamin D (25OHD) levels <20 ng/mL and 9 neonates (64.3%) had 25OHD levels <10 ng/mL. Twenty-one neonates had hypocalcemic tetany. The serum calcium and iCa concentrations of neonates with tetany were 4.2-8.3 mg/dL and 1.85-3.88 mg/dL, respectively. Three neonates showed symptomatic hypocalcemia with calcium levels over 7.5 mg/dL. Among the 16 neonates who underwent electroencephalography (EEG), 12 had abnormalities, which normalized after 1-2 months. CONCLUSION: Formula milk feeding, PTH insufficiency and low serum vitamin D concentration are associated with the development of neonatal hypocalcemia. Symptoms such as tetany and QT interval prolongation can develop in relatively mild hypocalcemia. Moreover, transient neonatal hypocalcemia can cause transient EEG abnormalities.

Blood glucose levels within 7 days after birth in preterm infants according to gestational age.

PURPOSE: This study investigated blood glucose levels in preterm babies according to gestational age (GA). METHODS: Subjects were 141 preterm infants with a GA<34 weeks. Data on blood glucose levels, GA, body weight, glucose infusion rate, and other contributing factors in the first 7 days after birth were analyzed. Hypoglycemia was defined as a blood glucose level of <40 mg/dL up to 24 hours after birth and as <50 mg/dL thereafter. Hyperglycemia was defined as a blood glucose level >180 mg/dL. RESULTS: During the 7 days after birth, hypo- and hyperglycemia occurred in 29 (29 of 141, 20.6%) and 42 (42 of 141, 29.8%) neonates, respectively. During the first 2 hours, 18 neonates (12.8%) exhibited hypoglycemia, and only 2 (2 of 141, 1.4%) developed hyperglycemia. From 6 to 24 hours, hypo- and hyperglycemia were observed in 0 and 9 (9 of 141, 6.4%) neonates, respectively. Infants small for their GA (SGA) were at risk for hypoglycemia both within 24 hours (odds ratio [OR], 2.718; P=0.045) and during days 2 to 7 (OR, 4.454; P=0.006), and hyperglycemia during days 2 to 7 (OR, 3.200; P=0.005). Low 1-minite Apgar score was risk factor for both hypo- and hyperglycemia during days 2 to 7 (OR, 0.756; P=0.035 for hypoglycemia and OR, 0.789; P=0.016 for hyperglycemia). Both hypo- and hyperglycemia within 24 hours were less common in those who started feeding (OR, 0.294; P=0.013 for hypoglycemia and OR, 0.162; P=0.011 for hyperglycemia). CONCLUSION: Careful blood glucose level monitoring is required in preterm infants, especially SGA infants or those with low Apgar score. Early feeding could be beneficial for maintaining euglycemia.